RESEARCH PAPER

Celiac Disease in Children with Moderate-to-Severe Iron-deficiency

Anemia
MANISH NARANG1, RAVIKUMAR NATARAJAN1, DHEERAJ SHAH1, AMARENDER SINGH PURI2, VIKAS MANCHANDA3
AND MRINALINI KOTRU4
From 1Division of Pediatric Gastroenterology, Department of Pediatrics and 4Department of Pathology,University College of
Medical Sciences and GTB Hospital; 2Department of Gastroenterology, GB Pant Institute of Post Graduate Medical Education and
Research;and 3Department of Clinical Microbiology and Infectious Diseases, Chacha Nehru Bal Chikitsalaya; Delhi, India

Correspondence to:
Dr Manish Narang, Professor,
Department of Pediatrics, UCMS and
GTB Hospital, Dilshad Garden,
Delhi 110095, India.
manish_2710@yahoo.com
Received: December 28, 2016;
Initial review: February 09, 2017;
Accepted: September 22, 2017.
Objective: To evaluate the proportion of children with moderate to severe iron-deficiency
anemia who have associated celiac disease. Methods: This cross-sectional analytical study
was conducted among children aged 1 to 12 years of age with moderate-to-severe iron
deficiency anemia and control children without anemia.Serum IgA-tissue trans-glutaminase
levels were assessed in both cases and controls. All children with positive celiac serology
underwent upper gastrointestinal endoscopy and duodenal biopsy; biopsy finding of Marsh
grade 3 was considered positive for celiac disease. Results: There were 152 anemic children
and 152 controls with mean (SD) hemoglobinof 7.7 (1.8) and 12.2 (0.74) g/dL, respectively.
16 (10.5%) cases and 3 (2%) control patients had positive serology for celiac disease [OR
(95% CI) 5.33 (1.52-18.67), P=0.007]. Six (3.9%) children with iron-deficiency anemia and
none of the controls had biopsy features diagnostic of celiac disease. Conclusion:In the
Northern Indian tertiary-care hospital outpatient setting, Celiac disease was associated with
4% of children presenting with moderate-to-severe anemia.
Keywords: Biopsy, Diagnosis, Endoscopy, Transglutaminases.

U
nexplained iron-deficiency anemia without
gastro-intestinal symptoms is a well-
recognized presentation of celiac disease
(CD) [1]. However, the data regarding the
proportional contribution of CD to unexplained anemia
in children are scarce, especially from a country like India
where nutritional anemias are very common [2]. Children
diagnosed with CD require major dietary modifications
in addition to the treatment of the nutritional anemia [3].
This study was conducted to assess proportionate
contribution of celiac disease as the underlying causative
factor of the iron deficiency anemia.
METHODS
This cross-sectional study was conducted in the pediatric
outpatient department of a tertiary-care center in Delhi
over a period of 18 months in 2013-15. Children between
the ages of 1 and 12 years with visible pallor as detected on
physical examination were included in the study if they
had moderate-to-severe iron-deficiency anemia (IDA).
Moderate anemia was defined as hemoglobin
concentration: 7-9.9 g/dL in children <5 years of age and
8-10.9 g/dL in children of 5 to 12 years of age. Severe
anemia was defined as hemoglobin concentration: <7 g/dL
in children <5 years of age; <8 g/dL in children of 5 to 12
years of age [4]. Iron-deficiency was considered as a cause
of anemia if serum ferritin level was <12 ng/mL and/or
transferrin saturation <16% [5,6]. Healthy siblings of
patients visiting the outpatient department were chosen as
controls.The controls consisted of children with normal
Accompanying Editorial: Pages 23-24.
hemoglobin level as per the age (hemoglobin>11 g/dL in
12-59 month, >11.5 g/dL in 5-11 years of age, >12 g/dL in
12 years of age) and normocytic normochromic cells.
Exclusion criteria were: severe acute infection
(pneumonia), chronic diseases (cardiac, renal, hepatic,
autoimmune disease, immunodefi-ciencies),
hematological disorders, chronic gastrointes-tinal
diseases, already diagnosed celiac disease, bleeding,
intake of any cytotoxic agents or radiotherapy in the last 6
weeks.
A detailed history with emphasis on current or past
gastrointestinal symptoms was taken from the children or
their parents. Nutritional status was assessed at the time
of entry into the study. All eligible anemic children

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NARANG, et al. CELIAC DISEASE IN ANEMIC CHILDREN

underwent hematological work-up that included
hemogram, peripheral blood smear, red blood cell
indices, serum iron levels, total iron binding capacity,
transferrin saturation and serum ferritin levels. Stool
examination was done on two consecutive days for
identification of parasitic infestations. Children who were
recruited as controls had a complete blood count done
prior to enrolment.
We measured IgA-anti tissue transglutaminase (IgA-
tTG) by ELISA (Aeskulisa) in all included patients. IgA-
tTG levels >18 U/mL were as considered positive as per
information provided by the manufacturer, levels between
12 and 18 U/mL were considered as equivocal, and levels
<12 U/mL were considered as negative. All children who
screened positive for celiac disease underwent upper
gastrointestinal (UGI) endoscopy. Four biopsy specimens
were taken from the second/first portion of the
duodenum, out of which at least one sample was taken
from the duodenal bulb. Histopathological examination
of duodenal biopsies was performed by a histopathologist
blinded to clinical history, and the result was graded using
the modified Marsh grading [7]. Final diagnosis of CD
was based on serology and endoscopic duodenal biopsy
(Grade-3). Children diagnosed as CD were adviced strict
gluten-free diet and oral iron supple-mentation for
nutritional anemia. Children with IDA were advised oral
iron preprations and dietary supplementation.
A sample size of 138 children with anemia (and 138
non-anemic controls) was calculated to determine the
proportion of celiac disease with an estimated proportion
of 10% [5] with absolute precision of 0.05 and
confidence interval of 95%. Assuming 10% loss to follow
up, 152 cases and control were recruited. The statistical
software SPSS 17 for Windows (Illinois, Chicago) was
used for statistical analysis. Fischer’s exact test was
applied to compare the proportion IgA-tTG positive
patients among cases and controls. Ethical clearance was
obtained from Institutional ethical committee of
University College of Medical Sciences. A written
informed consent was obtained from parents of children
eligible for inclusion, and assent was taken from children
≥7 years of age.

Children with visible pallor Children with normal

screened for low hemoglobin 241 hemoglobin approached 197
Excluded 89
Bleeding history 29
Acute infection 35 Excluded 45
Negative consent 10 Negative consent 32
Thalassemia trait 9 Thalassemia trait 9
Macrocytic anemia 4 Macrocytic anemia 4
Family history of CD 2

Cases (children with moderate Controls (children with normal

to severe IDA) 152 hemoglobin and NCNC RBC) 152

Serum tTG levels 152 Serum tTG levels 152

Positive tTG levels 16 Positive tTG levels 3

Lost to follow-up 1

UGI endoscopy and D2 biopsy 15 UGI endoscopy and D2 biopsy 3

Celiac disease 6 Celiac disease 0

CD: celiac disease; IDA: iron deficiency anemia; NCNC RBC: normocytic normochromic red blood cells; tTG: tissue transglutaminase; UGI: upper
gastro-intestinal; D2: second part of duodenum.

FIG.1 Study flow chart.

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NARANG, et al. CELIAC DISEASE IN ANEMIC CHILDREN

TABLE I DEMOGRAPHIC CHARACTERISTICS OF CHILDREN WITH TABLE IICOMPARISON OF ANEMIC PATIENTS WITH OR WITHOUT
AND WITHOUT ANEMIA CELIAC DISEASE
Cases (n=152) Controls (n=152) Celiac disease No celiac disease
(n=6) (n=146)
Gender (M:F) 1.33 1.23
#Age (mo) 41 (32.9) 86.9 (39.0) Wasting 0 16 (11%)
WAZ -1.06 (0.92) -0.93 (0.96) Stunting 0 30 (20.5%)
#HAZ #Hemoglobin (g/dL) 6.4 (1.13) 7.8 (1.80)
-1.41 (0.87) -1.12 (0.95)
WHZ -0.47 (1.36) -0.12 (1.51) *Severe anemia 5 (83.3%) 54 (37%)
MAC (cm) 15.20 (1.63) 16.63 (1.85) Moderate anemia 1 (16.6%) 92 (63%)
*Hemoglobin (g/dL) 7.71 (1.80) 12.2 (0.74) *P=0.02; All value in no (%) except #hemoglobin in mean (SD).

All value in mean (SD); WAZ: weight for age z score; HAZ: height for
age z score; WHZ: weight for height z score; MAC: midarm
circumference. *P=0.001; #P<0.01.
RESULTS
The flow of participants in the study is shown in Fig.1.
We included 152 cases and 152 controls. The non-anemic
controls were of higher age group as compared to anemic
cases [mean (SD): 86.9 (39) months vs 41 (32.9) months;
P=0.002] (Table I).
Increased prevalence of IgA-TTG was found among
anemic children, as compared to non-anemic controls (16
vs 3; P=0.007). Endoscopy was conducted in 18 children
(15 anemic), of which normal villous pattern was seen in
3 controls and 5 with anemia Marsh Grade I and grade
IIIb findings were seen in 6 and 2, respectively of the
anemic children. Two anemic children had giardiasis.
After UGI endoscopy and biopsy, six (3.9%) children
with moderate or severe anemia and none of the control
group were diagnosed as celiac disease (P=0.013).
Among 92 children with moderate anemia, one (1.08%)
patient had celiac disease while among 59 children with
severe anemia 5 (8.5%) had celiac disease. There was a
significant difference between the mean (SD)
hemoglobin level between patients with celiac disease
and patients without celiac disease [6.38 (1.13) g/dL vs
7.77 (1.80) g/dL; P=0.029]. Subgroup analysis between
anemic patients with or without celiac disease is
mentioned in Table II.
DISCUSSION
This cross-sectional study showed that celiac disease
accounted for 8.5% and 3.9% of children with severe and
moderate to severe iron deficiency anemia, respectively at
a tertiary-care hospital outpatient setting in Northern India.
Studies in children with iron-deficiency anemia are
limited [1,8,9]. A study by Ertekin, et al. [9] among
Turkish children had similar results with a mean
hemoglobin level significantly lower in IDA patients with
CD than in those without CD [9]. Moreover, those with
severe anemia had higher odds of having CD.
As prevalence of anemia in India children 6 months-
59 months is 58.4% [2], there is a greater chance of
missing those children with celiac disease presenting
atypically as anemia. Early identification of these
subclinical cases in childhood assumes greater
importance since these patients are at risk of malignancy
and mortality in later life and morbidity like the presence
of unsuspected nutritional deficiencies.
The major limitation of this study is that being a
hospital-based study results obtained in this study might
not be representative of the whole population. The
sample size was inadequate to find other clinical
predictors of celiac disease in anemic children. Not doing
IgA levels to screen for IgA deficiency, non-evaluation of
occult blood loss in stool, and controls not being age
matched are other study limitations. No loss to follow-up
and outcome assessment using endoscopy are the
strengths of the present study.
We conclude that anemic children, especially those
presenting with severe anemia have significantly higher
likelihood of having CD. Physicians treating children
with severe anemia may consider screening them for
celiac disease. We recommend community-based studies
to confirm these findings.

WHAT THIS STUDY ADDS?

• Severely anemic patients have higher chances of having associated celiac disease.

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NARANG, et al.
Contributors: MN: Study conception and manuscript writing;
RN: Data collection, analysis and manuscript writing; DS:
Study conception, and critical review of manuscript for
intellectual content; ASP, VM and MK: Study related
procedures (data collection), their interpretation and critical
inputs into manuscript.
Funding: None; Competing interests: None stated.
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